Patients homozygous for familial hypercholesterolemia (FH) manifest profound hypercholesterolemia, cutaneous cholesterol deposits termed xanthomas, and cholesterol deposition in a variety of tissues including the eye, tendons, and inside the arterial vessels. These patients experience accelerated atherosclerosis and develop symptomatic cardiovascular disease from the ages of 2-30 years, and many die before the age of 20. The cause for the 10 fold increase in total and low density lipoprotein (LDL) cholesterol concentrations is a defect in the ability of the body to extract the cholesterol-rich LDL particles from the circulation via the LDL receptor pathway. More than 300 mutations in the LDL receptor gene can lead to the loss of the expression of functional LDL receptors on the surface of liver cells. We have previously demonstrated that the degree of LDL receptor dysfunction on cultured skin fibroblasts from these patients highly correlates with the concentrations of LDL cholesterol present in their circulation. We have applied a variety of therapies to reduce the LDL cholesterol concentrations in these patients including diet, combination hypolipidemic drug therapy, portacaval shunting of the liver, plasma exchange, LDL apheresis, liver transplantation, and most recently adenoviral gene therapy. The degree of coronary artery atherosclerosis and the response to lipid-lowering intervention is variable among patients identified as having this condition. We are determining extent of disease and the progression of atherosclerosis by MRI, Electron Beam Tomography, and Intravascular Ultrasound in these patients. We have both developed novel means of quantitating human atheroma in vivo as well as demonstrate that assessment of the extent and severity of both cholesterol deposition into tissues and in atherosclerosis using computerized axial tomography. Loss of the function of the receptor for low density lipoproteins also abrogates vascular wall remodeling generally associated with atherogenesis. This array of testing has led to a new concept in atherosclerotic cardiovascular disease risk assessment, the cholesterol-years risk score. We have demonstrated that the cholesterol-year score is also effective in describing atherogenesis in patients in the Framingham Heart Study. These observations in this rare inborn error of lipoprotein metabolism have theoretic and practical implications for gene therapy in these patients as well as in individuals with more common forms of atherosclerosis.